tbuckley/cabot-search huggingface dataset:
Impact of paclitaxel versus docetaxel on neuropathy in ovarian cancer patients with diabetes.
Authors: Kaitlyn Kincaid, Teresa KL Boitano, Charles A. Leath, J Michael Straughn
Journal: Journal of Clinical Oncology (2022)

e17616 Background: Peripheral neuropathy is a common side effect of taxanes, particularly in diabetic patients, which can significantly affect quality of life. The objective of this study was to determine whether there was a difference in the incidence of new or worsening neuropathy between diabetic patients with ovarian cancer who received paclitaxel versus docetaxel as part of their primary therapy. Methods: This retrospective cohort study included ovarian cancer patients with Type I or Type II diabetes at a large academic institution who underwent surgery from 6/2016 to 5/2020 and received neoadjuvant and/or adjuvant chemotherapy. Individual chart review was performed to assess patient characteristics including race, body mass index (BMI), performance status (PS), Charlson Comorbidity Index (CCI), baseline hemoglobin A1c, current diabetic medications. The primary outcome was incidence of new or worsening neuropathy during primary therapy including adjuvant or neoadjuvant chemotherapy. New neuropathy was defined as no neuropathy prior to chemotherapy. Worsening neuropathy was defined as baseline neuropathy that worsened after initiation of chemotherapy. Secondary outcomes included chemotherapy treatment delay, increase of diabetic medications during therapy, and a change of chemotherapy regimen from paclitaxel to docetaxel. Statistical analysis was performed using SPSS v. 26. Results: 32 patients met inclusion criteria. Patient demographics including race, PS, BMI and CCI were similar between patients who received paclitaxel and those who received docetaxel. 24 patients (75%) received paclitaxel and 8 (25%) received docetaxel. The majority (93.8%) of patients had Type II diabetes. Patients who received paclitaxel were more likely to develop new or worsening neuropathy (81% v. 50%; p = 0.028) but less likely to require an increase of diabetic medications (0% v. 50%; p = 0.003) compared with patients receiving docetaxel. During primary therapy, 17% of patients were transitioned from paclitaxel to docetaxel due to treatment-related complications (i.e. neuropathy (50%), allergic reaction (50%)). There was no difference in incidence of treatment delays between the two treatment groups (25% v. 25%; p = 1.0). Conclusions: Patients with ovarian cancer who received paclitaxel were more likely to experience new or worsening neuropathy compared to patients who received docetaxel. There was no difference in treatment delays between the groups, but nearly one-fifth of patients receiving paclitaxel had to be transitioned to docetaxel because of treatment-related complications. Because of fewer side-effects, docetaxel is a reasonable chemotherapy alternative in ovarian cancer patients with diabetes.
Subclonal somatic copy number alterations emerge and dominate in recurrent osteosarcoma.
Authors: Michael David Kinnaman, Simone Zaccaria, Alvin Makohon-Moore, Gunes Gundem, Juan E. Arango Ossa, Nancy Bouvier, Filemon S. Dela Cruz, Meera Hameed, Julia Lynne Glade Bender, William D. Tap, Paul A. Meyers, Elli Papaemmanuil, Andrew Kung, Christine A Iacobuzio-Donahue
Journal: Journal of Clinical Oncology (2022)

11533 Background: Multiple large-scale tumor genomic profiling efforts have been undertaken in osteosarcoma, however little is known about the spatial and temporal intratumor heterogeneity and how it may drive treatment resistance. Methods: We performed 30-80x whole genome sequencing (WGS) of 37 tumor samples from 8 patients with relapsed or refractory osteosarcoma. A set of high confidence single nucleotide variants (SNV), copy number alterations (CNA), structural variations (SV) were called for each sample using our pediatric expanded genomics pipeline and an evolutionary analysis was performed using a custom pipeline of computational tools. Results: Of the 8 patients in our cohort, 4 had localized disease at diagnosis (OSCE4, OSCE5, OSCE6, OSCE9) and 4 had metastatic disease at diagnosis (OSCE1, OSCE2, OSCE3, OSCE10). There were 17 samples from primary sites, 7 were pretreatment biopsies, 10 from on therapy primary resections. 20 samples came from metastatic sites, 15 of which were from lung metastases. Driver gene SNV’s were identified in 5 of 8 patients, including TP53 (OSCE1), ATRX (OSCE3, OSCE10), RB1 (OSCE4), and CDKN2A (OSCE9). No new driver SNV’s emerged post-therapy in any patient. HATCHet, an algorithm which infers clone specific copy number alterations, identified subclonal CNAs in all but one patient (OSCE2). In the 7 patients with subclonal CNAs, 6 had two copy number clones identified, and 1 patient (OSCE10) had three copy number clones identified. In 5 patients (OSCE1, OSCE4, OSCE5, OSCE6, OSCE10) there is a copy number clone that is subclonal in the primary tumor which emerges and dominates at subsequent relapses. The resistant clone in each of these cases had either MYC gain/amplification. Amplifications in CCNE1 (OSCE1), RAD21 (OSCE4, OSCE5, OSCE10), VEGFA (OSCE1, OSCE9), IGF1R (OSCE6) were also identified as potential drivers in the resistant copy number clones. In two of these patients (OSCE1, OSCE6), the treatment resistant subclone becomes the dominant copy number clone by the time of primary resection. SNV based phylogenies revealed monoclonal and polyclonal seeding of metastases and monophyletic and polyphyletic modes of dissemination. Over half the new mutations acquired in recurrent disease were attributed to HRD or cisplatin mutational signatures. Conclusions: Subclonal copy number clones emerge and dominate in relapsed osteosarcoma, with MYC gain/amplification a defining characteristic in our cohort. Selective pressure from neoadjuvant chemotherapy reveals this clone at the time of primary resection, implying genomic profiling at this timepoint may be more reflective of its metastatic potential. [Table: see text]
The reduced environmental impact of American society of Clinical Oncology’s 2021 virtual annual meeting.
Authors: Katie Lichter, Sasha Demeulenaere, Taylor Drew, Emily Wong, Surbhi Grover
Journal: Journal of Clinical Oncology (2022)

e13625 Background: In response to the threat of the COVID-19 pandemic, the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting transitioned to a virtual, online conference. As medical conferences around the world have transitioned to virtual formats, numerous benefits have been uncovered; however, the environmental effect of reduced travel on carbon emissions remains largely unknown. Today, it is estimated that conference attendance accounts for 35% of a scientist’s total carbon footprint. Given that the climate crisis is a growing threat to human health and oncology outcomes, it is imperative to begin to quantify, understand, and promote sustainable practices. We aim to highlight the reduced travel-related greenhouse emissions associated with the transition of ASCO’s 2021 Annual Meeting to a virtual platform in comparison to a hypothetical in-person conference. Methods: Attendee demographic data was collected online from the ASCO 2021 Annual Meeting. The distance traveled per attendee to a hypothetical in-person conference in Chicago, Illinois (the location for the 2022 Annual Meeting) was estimated using reported attendees’ home country and a hypothesized centralized location. Approximate airline miles and associated carbon dioxide (CO 2 ) emissions were calculated using the Environmental Protection Agency’s Greenhouse Gas Tools. It was assumed that all attendees had non-stop airfare and traveled in economy class. The approximate CO 2 emissions for the virtual conference was estimated based on assumed internet usage (8 hours/day for the 5-day conference period). Results: A total of 32,950 conference attendees were identified - 14,150 domestic attendees and 16,050 international attendees. For the hypothesized in-person conference, the total carbon footprint for all assumed transportation was determined to be 28,468,031.25 lbs. of CO 2 emissions, with an average of 863.0 lbs. of CO 2 emissions per attendee. Alternatively, emissions related to virtual conference internet streaming accounted for a total of 436,258 lbs of CO 2 . Total emissions spared with the transition to a virtual platform was an estimated 28,031,773.25 lbs of CO 2 . , the equivalent emissions of 1,531 U.S. homes’ energy use for one year. Conclusions: Incorporating options for virtual attendance at academic conferences has the potential to significantly reduce carbon emissions. However, many believe that virtual networking cannot replace in-person interactions particularly for early-career attendees. Regardless, our professional societies have an obligation to investigate and promote greater sustainability of our annual meetings.
ARST2031: A study to compare early use of vinorelbine and maintenance therapy for patients with high risk rhabdomyosarcoma.
Authors: Wendy A Allen-Rhoades, Leo Mascarenhas, Wei Xue, Sarah S. Donaldson, Dana Casey, John Frederick Shern, Erin R. Rudzinski, Stephen Skapek, David A. Rodeberg, Timothy Lautz, Archana Shenoy, Irit Maianski, Sireesha Yedururi, Kim Maxa, Brian D. Crompton, Lindsey Fricke, Zhong Su, Douglas James Harrison, Rajkumar Venkatramani
Journal: Journal of Clinical Oncology (2022)

TPS11591 Background: Patients with high-risk rhabdomyosarcoma (HR-RMS) continue to have poor outcomes with 3-year event free survival (EFS) rates of 30% or less despite chemotherapy dose intensification on recent cooperative group RMS trials. Vinorelbine (VINO) has demonstrated clinical activity in RMS patients with relapsed/refractory disease and shown to provide a survival benefit when given with oral cyclophosphamide as maintenance chemotherapy for a select group of patients that achieved first complete remission. Methods: ARST2031 is a randomized Phase 3 trial with the primary aim to compare event-free survival (EFS) of patients with HR-RMS treated with vincristine, dactinomycin and cyclophosphamide (VAC) followed by maintenance with vinorelbine and oral cyclophosphamide (VINO-CPO) or vinorelbine, dactinomycin and cyclophosphamide (VINO-AC) followed by maintenance with VINO-CPO. Patients are stratified by histology and randomly assigned to VAC followed by VINO-CPO maintenance or VINO-AC followed by VINO-CPO maintenance. To be eligible, patients must be ≤ 50 years of age at the time of enrollment with newly diagnosed RMS except adult-type pleomorphic, based upon institutional histopathologic classification. All patients must have Stage 4 disease and patients diagnosed with embryonal RMS (ERMS) must be ≥ 10 years of age. Patients with malignant cytology in cerebrospinal fluid, intra-parenchymal brain metastases, or diffuse leptomeningeal disease are excluded. The study was activated on September 13, 2021 and is anticipated to enroll approximately 4 patients per month. The planned sample size is 100 patients, with approximately 50 patients randomized to each arm. Safety and feasibility of VINO-AC will be assessed in the first 8 patients prior to randomization. The study will have power of 0.8 to detect a hazard ratio of 0.61 (74 events in total) when the one-sided Type I error rate is 0.10, with 30 months of accrual and 2 years of follow-up. The hazard ratio of 0.61 was determined by assuming piecewise exponential distributions and specifying the 2-year EFS of 46% vs. 28% and long-term EFS of 32% vs. 16%, based on prior outcome data. Biospecimens will be collected and banked for future use. Clinical trial information: NCT04994132.
Constitutional MLH1 promotor hypermethylation: Clinical characteristics and testing frequency of a poorly recognized mechanism for Lynch-associated malignancies.
Authors: Rakesh Biswas, Tiffani DeMarco, Arthur Winer, Raymond Couric Wadlow, Jamie Randall, Misha Rashkin, Rhianna Urban, Timothy Lewis Cannon
Journal: Journal of Clinical Oncology (2022)

10581 Background: MSI-H colorectal cancer is most often a result of deleterious mutations in mismatch repair genes, but can also occur through repressed gene transcription due to hypermethylation of the MLH1 promoter, often associated with BRAF V600E mutations. However, there is a subset of patients who have a “constitutional epimutation”, resulting in hypermethylation of MLH1 throughout normal tissue. We observed a young patient develop a second primary Lynch associated malignancy (see Table 1) who was found to have a constitutional epimutation in MLH1 that prompted us to review the frequency with which the test was ordered and the positivity rate, as well as outline the clinical history in the positive cases. Methods: We reviewed all of the testing ordered for MLH1 hypermethylation of peripheral blood (MLHPB) at the Mayo Clinic Laboratory between 09/01/2020 and 09/01/2021. To the best of our knowledge, this is the only clinically available testing lab in the United States. We reviewed positive casesfor characteristics including the number of malignancies, age of diagnosis, and family history. Results: 33 MLHPB total tests were ordered in the United States at the Mayo Clinic laboratories between 09/01/2020 and 09/01/2021. Three of the tests were positive, including the single test ordered by our institution, and one of the two additional positive tests was available for detailed review. Our institution’s positive test case was a 41 year old women who developed T4N2M0 colorectal cancer 5 years after being treated for endometrial cancer. She had endometrial cancer with absence of MLH1 and PMS2 staining and had a negative germline cancer risk panel at age 36. Five years later, she developed a T4N2 colorectal cancer after which repeat germline testing with RNA sequencing was negative and she was found to have constitutional MLH1 promoter hypermethylation. We were able to obtain clinical information about two of the three individuals with positive tests (See Table). Conclusions: Recognition of constitutional MLH1 hypermethylation may allow for earlier recognition of Lynch related malignancies in affected patients and families. Testing appears infrequent and this condition often goes unrecognized. Specific consensus guidelines may improve recognition and cancer screening in this population. [Table: see text]
Evaluation of stage IV pancreatic adenocarcinomas based on mutational profiling of tumors.
Authors: Katherine E Poruk, Amber Moran, Vicki Doctor, Julia Andrea Elvin, Saba Radhi, Arturo Loaiza-Bonilla, Julian C. Schink, Maurie Markman
Journal: Journal of Clinical Oncology (2022)

4139 Background: Curative treatment of pancreatic adenocarcinoma (PDAC) remains a challenge, as most patients present with advanced disease that has spread to other organs. The main opportunity for cure for these individuals remains systemic therapy. An improved understanding of the tumor biology is needed to appropriately target therapies for individual patients. We present cohort of Stage IV PDAC patients who underwent prospective comprehensive genomic profiling (CGP) in a national cancer network to evaluate genomic mutations, treatment patterns and survival. Methods: Between 2013 and 2021, 458 patients with Stage IV PDAC underwent CGP with hybrid capture of up to 406 cancer-related genes on tumor tissue for treatment decision-making. Clinically relevant genomic alterations (CRGA) were defined as associated with targeted therapies or mechanism-driven clinical trials. Patient demographics and outcomes were retrospectively reviewed with IRB approval. Results: Median patient age at presentation was 59 years (range, 26-84) and a majority were male (55%). Median overall survival was 15 months. Most patients were treated with first line chemotherapy, predominantly gemcitabine or FOLFIRINOX. GA were identified in 98% (n = 447) of PDAC patients. The most common genomic alterations were in KRAS (85%), TP53 (75%), CDKN2A (52%), SMAD4 (21%), ARID1A (9%), BRCA2 (5%), RNF43 (4%), and BRCA1 (1%). A mutation in one of the four commonly mutated genes ( KRAS, TP53, CDKN2A, or SMAD4) was identified in 94% (n = 426). Median overall survival was significantly worse for patients with mutations in KRAS or TP53 (both, P &lt; 0.05). 185 patients (40%) had an actionable mutation based on the Know Your Tumor registry trial, including mutations in BRCA1, BRCA2, BRAF, CHEK2, ATM, ATK and STK11. MSI status was noted for 226 patients; only one patient was MSI-high. Tumor Mutational Burden (TMB) was known for 228 patients and was split as follows: 199 TMB-low (87%), 27 TMB-intermediate (12%), and 2 TMB-high (1%). TMB status was not associated with OS (P = 0.21). PD-L1 status was obtained in 20 patients, with 9 PD-L1 positive (45%); this was not associated with OS (P = 0.66). Of the 38 patients with a BRCA1 or BRCA2 mutation, 31 (82%) were treated with Olaparib. Other commonly utilized therapies included Niraparib (n = 56), Regorafenib (n = 8), Everolimus (n = 34), Erlotinib (n = 8), and Cetuximab (n = 6). Conclusions: In a large series of Stage IV PDAC patients assayed with CGP, GA were identified in 98% of tumors but only 40% had an actionable mutation. Most patients continue to be treated with conventional chemotherapy despite a sizeable group with targetable mutations. Further work is needed to identify targeted therapies for the more common mutations in PDAC given their impact on overall survival.
Trial in progress: Phase 1b/3 study of bemarituzumab + mFOLFOX6 + nivolumab versus mFOLFOX6 + nivolumab in previously untreated advanced gastric and gastroesophageal junction (GEJ) cancer with FGFR2b overexpression (FORTITUDE-102).
Authors: Zev A. Wainberg, Eric Van Cutsem, Markus H. Moehler, Yoon-Koo Kang, Priscilla Yen, Elizabeth Finger, Alissa Keegan, Kohei Shitara
Journal: Journal of Clinical Oncology (2022)

TPS4165 Background: Fibroblast growth factor receptor 2b (FGFR2b) is overexpressed in approximately 30% of non-human epidermal growth factor receptor 2 (non-HER2) positive gastric cancer (Wainberg, 2021). Bemarituzumab is a first-in-class monoclonal antibody that specifically blocks FGFR2b, inhibiting downstream tumor proliferation and enhancing antibody dependent cellular cytotoxicity (Catenacci, 2020; Xiang, 2021). In the phase 2 FIGHT study (Wainberg, 2021; Catenacci, 2021), progression-free survival (PFS) was improved (HR, 0.68; 95% CI, 0.44-1.04; p = 0.07) and a 5.7 month longer median overall survival (OS) was observed (19.2 months vs 13.5 months; HR, 0.60; 95% CI, 0.38-0.94) with bemarituzumab + mFOLFOX6 vs placebo + mFOLFOX6. Preclinical studies indicate that bemarituzumab modulates the tumor microenvironment to sensitize tumors to anti-PD1 monoclonal antibodies (Powers, 2016; Xiang, 2021) providing rationale for combination with nivolumab. Methods: FORTITUDE-102 (NCT05111626) is a phase 1b/3 study in patients (pts) with unresectable locally advanced or metastatic gastric or GEJ adenocarcinoma not amenable to curative therapy. Part 1 is an open-label safety lead-in; Part 2 is a double-blind, placebo-controlled study to evaluate efficacy and safety. Approximately 702 pts ≥18 years will be enrolled (Part 1, ̃20; Part 2, ̃682). Key eligibility criteria include Eastern Cooperative Oncology Group performance status 0-1, evaluable disease per RECIST v1.1, adequate hematologic and organ function, and no contraindication to receive mFOLFOX6 chemotherapy or nivolumab; for part 2, IHC-confirmed FGFR2b overexpression by central testing is required and no prior treatment for metastatic or unresectable disease allowed except 1 dose of mFOLFOX6 ± nivolumab. Key exclusion criteria include positive HER2 status and untreated or symptomatic CNS metastasis and leptomeningeal disease. Pts on bemarituzumab will receive 15 mg/kg every 2 weeks (Q2W) with an additional 7.5 mg/kg dose on cycle 1 day 8. mFOLFOX6 + nivolumab will be at a fixed dose Q2W. The dose-limiting toxicity (DLT) period is 28 days; observed safety data will influence additional enrollment to Part 1, de-escalation of bemarituzumab, or the recommended phase 3 dose (RP3D). For Part 1, primary endpoints are DLTs and adverse events; secondary endpoints include OS, PFS, and objective response (OR). For Part 2, pts will be randomized 1:1 to mFOLFOX6 + nivolumab Q2W plus either bemarituzumab at RP3D or placebo. Primary endpoint for Part 2 is OS; secondary endpoints include PFS, OR, and safety. The concurrent phase 3 FORTITUDE-101 study (NCT05052801) will evaluate bemarituzumab + mFOLFOX6 vs placebo + mFOLFOX6. Clinical trial information: NCT05111626.
Radiographic progression in the absence of prostate-specific antigen (PSA) progression in patients with metastatic hormone-sensitive prostate cancer (mHSPC): Post hoc analysis of ARCHES.
Authors: Andrew J. Armstrong, Nicolas Mottet, Taro Iguchi, Russell Zelig Szmulewitz, Jeffrey Holzbeierlein, Arnauld Villers, Antonio Alcaraz, Boris Alekseev, Neal D. Shore, Francisco Gomez-Veiga, Brad Rosbrook, Fabian Zohren, Ho-Jin Lee, Gabriel P. Haas, Arnulf Stenzl, Arun Azad
Journal: Journal of Clinical Oncology (2022)

5072 Background: Enzalutamide (ENZA) + androgen deprivation therapy (ADT) significantly reduced the risk of radiographic progression and increased overall survival in men with mHSPC, regardless of baseline PSA levels (ARCHES; NCT02677896). This post hoc analysis investigated concordance between PSA progression and radiographic progression in patients with mHSPC. Methods: Patients with mHSPC (n=1150) were randomized 1:1 to ENZA (160 mg/day) + ADT or placebo (PBO) + ADT. The concordance between radiographic progression and PSA progression, as defined by Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria, and between any rise in PSA above nadir was assessed. Results: In total, 267/1150 patients in ARCHES had radiographic progression (ENZA + ADT, n=79; PBO + ADT, n=188). At radiographic progression, the median (range) PSA for ENZA + ADT-treated patients was 2.25 ng/mL (0–1062.3 ng/mL) and 17.47 ng/mL (0–1779.5 ng/mL) for PBO + ADT-treated patients. Most patients (67%) treated with ENZA + ADT did not have PCWG2-defined PSA progression at radiographic progression, compared with 43% of those treated with PBO + ADT (Table). The median absolute and percentage rise in PSA from nadir to radiographic progression was 0.77 ng/mL and 200%, respectively, with ENZA + ADT compared with 12.23 ng/mL and 367%, respectively, with PBO + ADT. Conclusions: In this post hoc analysis of ARCHES, we found frequent discordance between radiographic progression and PSA progression by PCWG2 criteria or any PSA rise over nadir in patients with mHSPC treated with ENZA + ADT. Thus, regular imaging is recommended to detect radiographic progression among patients treated with potent androgen receptor pathway inhibitors, such as ENZA + ADT, as serial PSA monitoring alone may not be sufficient to detect radiographic progression in many patients. Clinical trial information: NCT02677896. [Table: see text]